Intellectual disability (ID) is a common disability affecting 2-3% of the general population. X-linked ID (XLID) disorders, caused by defects of genes on the X chromosome, affect 1.7 of 1,000 males. Patients with ID require long-term family involvement, medical care and social services with enormous attendant burden and cost. XLID is a medically important and biologically significant group of disorders for which the prospects for further progress on the understanding of their molecular basis using traditional genetic approaches are low. The availability of finished sequence for the X chromosome and the enormous capability of the next generation sequencing methods offer an exciting new opportunity to identify the genetic bases of this highly heterogeneous group of disorders. The fact that males have a single X chromosome makes these disorders especially attractive targets for a large scale sequencing approach. Using next generation sequencing and gene expression analysis, this study intends to (1) obtain DNA sequence of all recognized, functionally important segments of the euchromatic portion of the X chromosome in probands from 35 known X-linked ID entities, (2) identify a minimum of 15 novel XLID genes, and (3) establish genotype/phenotype correlations for the novel XLID genes discovered in this project. Identification of genes that cause XLID is essential for clinical diagnosis, counseling, prevention, clinical management, and a rational development of effective novel treatments. Understanding the pathogenesis of ID will provide valuable insight into the mechanisms for normal development of human cognitive functions. We anticipate that the results of this study will lead to (1) new research projects to understand the function of these XLID genes in intellectual function; (2) novel molecular diagnostic methods; (3) innovative strategies for disease prevention and treatment; and (4) major and lasting economic and social impacts on the affected individuals, their families, and society.